The overall objective for the proposal is to provide data which will permit the rational design of future sudden death intervention trials in man and allow the rational clinical use of existing and newly available antiarrhythmic agents. Three comprehensive studies are proposed. First, a study comparing the efficacy and toxicity of tocainide, propranolol, and quinidine. This study incorporates careful statistical design, multiple drug dose levels, frequent blood sampling to determine drug concentration, and quantitation of ventricular arrhythmias on ambulatory electrocardiograms and compares the efficacy of these agents in a group of patients with coronary artery disease exhibiting significant levels of ventricular premature beats. Second, an in-depth study of disopyramide. This study uses pharmacokinetically designed, individualized, intravenous drug infusions to achieve four separate steady-state drug concentrations. Antiarrhythmic effect is measured as reduction in premature ventricular contraction frequency during these infusions, compared to placebo infusions. The importance of plasma protein binding and metabolites will also be evaluated. Third, a study designed to determine the dynamics of pharmacologic activity of acebutolol, a new beta-blocking drug, and its acetyl metabolite, which is present during oral therapy at plasma concentration higher than acebutolol itself. This study utilizes the observation of differences in amounts of metabolite formed following intravenous compared to oral dosing and of differences in rates of decline of plasma concentration of these two compounds following oral administration, to define separate concentration-response curves for each compound and derive expressions to describe the dynamics of their combined pharmacologic effect.